The invention relates to an agent which can be applied topically and which contains hyaluronate lyases for penetration modulation of one or more active substances and/or medicaments for cosmetic and medical treatment of skin, mucosa, hair and/or nails, such as e.g. for treatment of diseases or functional disorders of human or animal skin, mucosa, hair and/or nails.
Medicaments and/or active substances are used together with auxiliary substances in the form of liquid, semi-solid or even solid formulations of differing composition for the treatment, prophylaxis and metaphylaxis of functional and structural disorders of the skin and/or mucosa. In dependence on the physicochemical properties of the active substance or medicament, of the base used and of the auxiliary substances contained therein as well as of the nature of the area of the skin to be treated, the active substance molecules penetrate via different penetration mechanisms into the skin; in the given case they penetrate the latter until they are re-absorbed by the vascular system.
The skin is characterised by its natural function as a barrier in relation to its surroundings. Thus it can counteract the penetration of externally applied substances and/or substance mixtures. The active substances and/or medicaments used or respectively the co-applied auxiliary substances must overcome the barrier of the stratum corneum in order to spread the effect in the desired tissue layer (epidermis, dermis or even in the follicles and the vascular system).
It has already been known for a long time that through the presence of one or more special auxiliary substances the penetration of active substances can be made easier (penetration modulation). These substances are here in a position to alter, via different active mechanisms which are to some extent not completely clarified, the penetration or permeation of active substances and/or medicaments.
The following have what is termed an xe2x80x9cenhancer effectxe2x80x9d: dimethyl sulphoxide, dimethyl acetamide, dimethyl formamide, derivatives of polyethylene glycol and propylene glycol, polyoxyethylene ester, alkanolamides, alkanolamines, alkylamines, N-alkylpyrrolidones, diethylene glycol monoethyl ether or fatty acid glycol esters (U.S. Pat. No. 5,912,009), 1-dodecylazacycloheptane-2-one, menthol (U.S. Pat. No. 4,933,184), plant oils (U.S. Pat. No. 5,229,130) isopropyl myristate (U.S. Pat. No. 5,618,555), eucalyptus oil (U.S. Pat. No. 4,440,777), fatty acid esters of lactic acid (U.S. Pat. Nos. 5,882,676 and 5,952,000) and lecithin (U.S. Pat. No. 4,783,450).
In U.S. Pat. No. 5,296,222 is described a percutaneous release system which contains lactam compounds (e.g. 1-substituted azacycloheptane-2-one) and propylene glycol. U.S. Pat. Nos. 3,989,816 and 4,316,893 also describe the application of lactam compounds.
In the Japanese disclosure Pat. Ser. No. 91-251534, are described plasters with increased penetration capability for piroxicam through the presence of polyoxyethylene alkyl ether or alkanolamides as penetration accelerators for the basic medicament triacetin (U.S. Pat. No. 58,834,010). Additional penetration accelerators are proposed in U.S. Pat. No. 4,755,535 (azacycloalkene), U.S. Pat. No. 4,699,77 (1-dodecylazacycloheptan-2-one and urea to absorb albuterol), U.S. Pat. No. 4,820,711 and U.S. Pat. No. 4,557,934 (medicaments dissolved in Azone or Azone derivatives).
The protective rights U.S. Pat. No. 5,914,322 and U.S. Pat. No. 5,962,433 describes agents which can be used topically and which have therapeutic application in pathological and traumatic symptoms of the skin, in which hyaluronic acid is used to facilitate transport of the active substance. The compositions named in U.S. Pat. Nos. 5,624,916 and 5,631,242 contain hyaluronic acid, urea and a pharmaceutical auxiliary and/or active substance with broad application for treating different skin and mucosa diseases.
To increase the penetration of hydrophilic substances, enzymes have also been proposed as penetration accelerators. The penetration-enhancing property of hyaluronidase of animal origin, especially obtained from bovine testes, is known. It is used for example in ointment form [Steinhaus, Christian and Sperandio, J. Amer. Pharmac. Assoc. Sci. Edit. 44,483 (1955) and Kalentey and Stenszky, Pharmazie 15,158, (1960)].
A transdermal release system having penetration accelerators is described in the French protective rights numbers 2,448,903 and 2,556,218. The transdermal agents contain in addition to the medicaments or active substances such as e.g. an antibiotic (tetracyline) and/or a local anaesthetic (lidocaine) and/or anti-inflammatory medicaments and/or an emulsifying or a mucolytic active substance, vitamin A and, as an auxiliary substance, sodium glycerol stereate and/or a plurality of enzymes as penetration-enhancing additives. Hyaluronidase, streptokinase, streptodornase, trypsin, chymotrypsin, alph-chymotrypsin, alpha-amylase, bromelain, papain, deoxyribonuclease, collagenase and subtilisin have been proposed as enzymes.
Disadvantageous about the known systems for enhancing penetration is that they can lead to irritations of the skin. The presence of proteases, and also of the solvents proposed as penetration accelerators, leads in some degree to direct damage of the skin. When hyaluronidases of bovine origin are used, there is the risk of transmitting infectious or antigenic material since generally speaking they still contain large amounts of other animal proteins (also other enzymes). The U.S. Pat. No. 4,152,212 proposes an intensive purifying process for a raw product of a hyaluronidase obtained from bovine testes or from liver tissue.
What is disadvantageous inter alia about the use of the bovine testes hyaluronidase and also of other hyaluronidases of animal origin is that the enzyme, as a result of the high foreign protein content, leads even after expensive purifying steps only to a product with low specific activity. Thus per cm2 of skin only activities smaller than 1,000 IU can be applied. In the meantime preparations from bovine products to be applied in humans are hardly used any more on account of the high risk of transmitting bovine spongiform encephalopathy (BSE). What is furthermore disadvantageous is that the hyaluronidase is strongly inhibited by sulphated glycosaminoglycans which occur in the skin and generally in the extra-cellular matrix. Thus the activity of the enzyme in the skin when used as a penetration enhancer is substantially worsened.
Proceeding from this, the object of the present invention is to quote an agent for topical application, which makes possible an effective promotion of penetration of the active substances or medicaments contained in the agent. The agent should preferably be able to be used for therapeutic treatment and/or control of the function of the skin or mucosa.
This object preferably is achieved according to the invention. Advantageous embodiments and developments of the invention will be apparent from the description of the invention provided herein.